Obesity is a serious illness with a complex etiology and a major risk factor for type II diabetes. Although obesity is common, the causes of obesity are poorly understood. A number of peripheral hormones and central neuropeptides have been implicated in the pathogenesis of obesity. Using PCR-differential display, we recently discovered that the mRNA in the neuropeptide melanin- concentrating hormone (MCH) is increased in the hypothalamus of ob/ob mice. In addition, MCH mRNA levels are regulated by fasting. To confirm that MCH is also increased and functions as an orexigenic factor, rats were injected with MCH-treated analogs through cannulas placed in the lateral ventricle in both normal and ob/ob animals. MCH induces an acute and profound increase in chow consumption. MCH also interacts with the melanocortin system. In fish, MCH induces melanosome aggregation while MSH induces dispersion. In mammals, the two peptides are antagonistic on a number of behaviors, and we have found that MCH and MSH act as mutual antagonists in a feeding paradigm. Unlike agouti, another inhibitor of MSH, MCH does not act on any of the known melanocortin receptors. MCH neurons, which are localized to the lateral hypothalamus project diffusely throughout the brain. Little is known about which specific areas of the brain parenchyma may be important in mediation MCH action. Virtually nothing is known about the MCH receptor, or about MCH-mediated signal transduction. Our preliminary data in scales from the common carp indicate that MCH does not act through cAMP or cGMP, but that it stimulates PI 3- kinase activity. The investigators propose to analyze the neuroanatomical basis of MCH action by performing functional and mapping studies, and we will couple these studies with analysis aimed at understanding the mechanism of its physiological action. Finally, we will analyze the effect of MCH gene ablation in a MCH knockout mouse.